Megaloblastic Anaemia (MA)

Abstract

Megaloblastic Anaemia (MA) is caused by retarded purine and pyrimidine (notably thymidylate) synthesis. Therefore DNA does not replicate, but RNA and protein (including haemoglobin) synthesis continues leading to typical cell changes, especially in rapidly dividing tissues such as the bone marrow, testicles, gastrointestinal and bronchial epithelia. Excepting some rare metabolic errors, MA is due to lack of or inability to absorb or to deliver to tissues and subcellular structures folate (FA) or cobalamin (Cbl or vitamin B12) or to produce enzymes which contain their coenzyme forms. Typical changes in the peripheral blood are pancytopenia, high MCV, MCH and red cell diameter (MCD) indexes and granulocytes with polylobulated nuclei. Low haemoglobin concentration is a late sign of deficiency. Specific treatment causes reticulocytosis and haematological remission, probably the most reliable diagnostic evidence for deficiency. In Cbl deficiency there is typical neurological damage; in children especially the brain is vulnerable. The mechanism causing MA (which does not occur in non-primates) is a disturbance in the regeneration of active tetrahydrofolate (THFA) needed for transfer of one-carbon units. Methyl-Cbl is a cofactor in the transfer of methyl from 5-methyl-THFA to homocysteine (Hcy), which becomes methionine. The latter is then converted to S-adenosylmethionine and used for methylation reactions. Serum-Hcy increases both in folate and Cbl deficiency. Deoxyadenosyl-Cbl (Ado-Cbl) is a mitochondrial coenzyme needed for the conversion of methylmalonyl-CoA to succinylCoA, then processed in the Krebs cycle. In Cbl deficiency, serum-methylmalonate (MMA) increases. Accordingly, Hcy and MMA are used to diagnose FA and Cbl deficiency. The mechanism causing the neurological damage in Cbl deficiency is not quite clear, MMA may damage the myelin sheaths. The traditional ways of diagnosing these deficiencies is to assay serum Cbl and FA and red cell FA (all mixtures of numerous compounds), then to investigate the cause of the deficiency by measuring radiovitamin-B12 absorption (especially the Schilling test), assaying intrinsic factor (IF) antibodies, performing gastric function tests, etc. During recent years, transcobalamin (TC or TCII) bound Cbl has become popular as the rest of the serum vitamin is bound to haptocorrin (HC, R-protein or TCI) and does not reflect the rapidly mobilizable body stores. At present there is no generally accepted gold standard test for diagnosing Cbl or FA deficiency, nor agreement on decision limits. The matter is complicated by the fact that based on the tests and therapeutic trials, large sectors of the population, especially the aged, have been considered to suffer from FA or Cbl deficiency, which may manifest itself as atherosclerosis, mental retardation, Parkinson’s disease, osteoporosis and infertility, maybe even problems with vision. In addition to low intake and gastric and pancreatic maldigestion, possible components in the causation of these conditions are slowly functioning genetic variants of enzymes and transport proteins involved in the metabolism of the vitamins. As lack of FA during pregnancy is known to cause neural tube defects, fortification of foodstuffs has been instituted, /a debatable practice, as FA tends to worsen the neurological damage in Cbl deficiency. Considering the very large sectors of the general population suspected to be deficient, the cost of the tests and their fallacies, one might consider prophylactic treatment of selected groups with FA and Cbl,